Hepatitis B virus (“HBV”) is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown, although it is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis and cell regeneration associated with the infection.
Hepatitis B virus has reached epidemic levels worldwide. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute viral hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver and hepatocellular carcinoma, a primary liver cancer. In western industrialized countries, high risk groups for HBV infection include those in contact with HBV carriers or their blood samples. The epidemiology of HBV is in fact very similar to that of acquired immunodeficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or HIV-associated infections. However, HBV is more contagious than HIV.
Daily treatments with α-interferon, a genetically engineered protein, have shown promise. A human serum-derived vaccine has also been developed to immunize patients against HBV. Vaccines have been produced through genetic engineering. While the vaccine has been found effective, production of the vaccine is troublesome because the supply of human serum from chronic carriers is limited, and the purification procedure is long and expensive. Further, each batch of vaccine prepared from different serum must be tested in chimpanzees to ensure safety. In addition, the vaccine does not help the patients already infected with the virus.
An essential step in the mode of action of purine and pyrimidine nucleosides against viral diseases, and in particular, HBV and HIV, is their metabolic activation by cellular and viral kinases, to yield the mono-, di- and triphosphate derivatives. The biologically active species of many nucleosides is the triphosphate form, which inhibits DNA polymerase or reverse transcriptase, or causes chain termination.
A number of synthetic nucleosides have been identified which exhibit activity against HBV. The (−)-enantiomer of BCH-189 (2′,3′-dideoxy-3′-thiacytidine), known as 3TC, claimed in U.S. Pat. No. 5,539,116 to Liotta, et al., is currently in clinical trials for the treatment of hepatitis B. See also EPA 0 494 119 A1 filed by BioChem Pharma, Inc.
β-2-Hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane (“FTC”), claimed in U.S. Pat. Nos. 5,814,639 and 5,914,331 to Liotta et al., exhibits activity against HBV. See Furman et al., “The Anti-Hepatitis B Virus Activities, Cytotoxicities, and Anabolic Profiles of the (−) and (+) Enantiomers of cis-5-Fluoro-1-{2-(Hydroxymethyl)-1,3-oxathiolane-5-yl}-Cytosine” Antimicrobial Agents and Chemotherapy, December 1992, page 2686-2692; and Cheng, et al., Journal of Biological Chemistry, Volume 267(20), 13938-13942 (1992).
U.S. Pat. Nos. 5,565,438, 5,567,688 and 5,587,362 (Chu, et al.) disclose the use of 2′-fluoro-5-methyl-β-L-arabinofuranolyluridine (L-FMAU) for the treatment of hepatitis B and Epstein Barr virus.
Penciclovir (PCV; 2-amino-1,9-dihydro-9-{4-hydroxy-3-(hydroxymethyl)butyl}-6H-purin-6-one) has established activity against hepatitis B. See U.S. Pat. Nos. 5,075,445 and 5,684,153.
Adefovir (9-{2-(phosphonomethoxy)ethyl} adenine, also referred to as PMEA or {{2-(6-amino-9H-purin-9-yl)ethoxy}methylphosphonic acid), also has established activity against hepatitis B. See, for example, U.S. Pat. Nos. 5,641,763 and 5,142,051.
Yale University and The University of Georgia Research Foundation, Inc. disclose the use of L-FDDC (5-fluoro-3′-thia-2′,3′-dideoxycytidine) for the treatment of hepatitis B virus in WO 92/18517.
Other drugs explored for the treatment of HBV include adenosine arabinoside, thymosin, acyclovir, phosphonoformate, zidovudine, (+)-cyanidanol, quinacrine, and 2′-fluoroarabinosyl-5-iodouracil.
U.S. Pat. Nos. 5,444,063 and 5,684,010 to Emory University disclose the use of enantiomerically pure β-D-1,3-dioxolane purine nucleosides to treat hepatitis B.
WO 96/40164 filed by Emory University, UAB Research Foundation, and the Centre National de la Recherche Scientifique (CNRS) discloses a number of β-L-2′,3′-dideoxynucleosides for the treatment of hepatitis B.
WO 95/07287 also filed by Emory University, UAB Research Foundation, and the Centre National de la Recherche Scientifique (CNRS) discloses 2′ or 3′ deoxy and 2′,3′-dideoxy-β-L-pentofuranosyl nucleosides for the treatment of HIV infection.
WO96/13512 filed by Genencor International, Inc., and Lipitek, Inc., discloses the preparation of L-ribofuranosyl nucleosides as antitumor agents and virucides.
WO95/32984 discloses lipid esters of nucleoside monophosphates as immuno-suppresive drugs.
DE 4224737 discloses cytosine nucleosides and their pharmaceutical uses.
Tsai et al., in Biochem. Pharmacol. 1994, 48(7), 1477-81, disclose the effect of the anti-HIV agent 2′-β-F-2′,3′-dideoxynucleoside analogs on the cellular content of mitochondrial DNA and lactate production.
Galvez, J. Chem. Inf. Comput. Sci. 1994, 35(5), 1198-203, describes molecular computation of β-D-3′-azido-2′,3′-dideoxy-5-fluorocytidine.
Mahmoudian, Pharm. Research 1991, 8(1), 43-6, discloses quantitative structure-activity relationship analyses of HIV agents such as β-D-3′-azido-2′,3′-dideoxy-5-fluorocytidine.
U.S. Pat. No. 5,703,058 discloses (5-carboximido or 5-fluoro)-(2′,3′-unsaturated or 3′-modified) pyrimidine nucleosides for the treatment of HIV or HBV.
Lin et al., discloses the synthesis and antiviral activity of various 3′-azido analogues of β-D-nucleosides in J. Med. Chem. 31(2), 336-340 (1988).
WO 00/3998 filed by Novirio Pharmaceuticals, Ltd. discloses methods of preparing substituted 6-benzyl-4-oxopyrimidines, and the use of such pyrimidines for the treatment of HIV.
Novirio Pharmaceuticals, Ltd. was also first to disclose 2′-deoxy-β-L-erythropentofuranonucleosides, and their use in the treatment of HBV in WO 00/09531. A method for the treatment of hepatitis B infection in humans and other host animals is disclosed that includes administering an effective amount of a biologically active 2′-deoxy-β-L-erythro-pentofuranonucleoside (alternatively referred to as β-L-dN or a β-L-2′-dN) or a pharmaceutically acceptable salt or prodrug thereof, including β-L-deoxyribothymidine (β-L-dT), β-L-deoxyribocytidine (β-L-dC), β-L-deoxyribouridine (β-L-dU), β-L-deoxyriboguanosine (β-L-dG), β-L-deoxyriboadenosine (β-L-dA) and β-L-deoxyriboinosine (β-L-dI), administered either alone or in combination, optionally in a pharmaceutically acceptable carrier. 5′ and N4 (cytidine) or N6 (adenosine) acylated or alkylated derivatives of the active compound, or the 5′-phospholipid or 5′-ether lipids were also disclosed.
Various prodrugs of antivirals have been attempted. Most notably, U.S. Pat. No. 4,957,924 to Beauchamp discloses various therapeutic esters of acyclovir.
In light of the fact that hepatitis B virus has reached epidemic levels worldwide, and has severe and often tragic effects on the infected patient, there remains a strong need to provide new effective pharmaceutical agents to treat humans infected with the virus that have low toxicity to the host.
Therefore, it is an object of the present invention to provide compounds, compositions and methods for the treatment of human patients or other hosts infected with HBV.